Organ-Specific Determinants of Tolerance and the Unique Challenge of Vascularized Composite Allotransplantation

Preclinical and clinical data demonstrate that solid organs differ markedly in their intrinsic antigenicity, inflammatory profiles, and thresholds for tolerogenic conditioning. Intraabdominal organs such as the kidneys and liver are inherently more permissive to tolerance, whereas hearts and lungs remain tolerance-resistant. These organ-specific disparities help understand why chimerism-based protocols that reliably induce renal tolerance often fail in thoracic organs, underscoring the necessity of interpreting tolerance strategies through an organ-specific rather than organ-agnostic lens (3). For instance, kidneys are consistently the most amenable organs for tolerance induction: in both NHP models and haplomatched human recipients, mixed hematopoietic chimerism, often transient, has been sufficient to achieve longterm, immunosuppression-free renal allograft survival (4)(5)(6). In fact, kidneys are often considered to possess a protolerogenic potential, a concept further supported by recent MGH findings showing kidney-induced cardiac allograft tolerance in the NHP model (7). In striking contrast, other solid organs such as the heart (8) and lung grafts remain considerably more refractory, necessitating often stronger immunosuppressive regimens. Cardiac and pulmonary grafts exhibit heightened ischemia-reperfusion injury, stronger innate immune activation, and more proinflammatory tissue-resident leukocyte compartments. These features drive accelerated effector priming, stronger indirect allorecognition, and a limited capacity to sustain donor hematopoietic engraftment, making these organs disproportionately resistant to both chimerism-based and regulatory-cell-based strategies (3). These mechanistic observations underscore that tolerance induction is fundamentally shaped by organ-intrinsic biology, with mixed chimerism proving far more stable and effective in kidneys and liver than in thoracic organs.These disparities become even more pronounced when considering vascularized composite allotransplantation (VCA). High immunosuppressive requirements have, to date, drastically limited the number of VCA procedures performed worldwide (9), and this translates into a particular complexity when applying tolerance-induction strategies to these grafts. VCAs contain multiple, highly antigenic, leukocyte-rich tissues, including skin and mucosa, as well as ischemia-sensitive components such as muscle. This places them at the extreme end of the tolerance-resistance spectrum. In swine, transient mixed chimerism is insufficient to induce full VCA tolerance, and a characteristic split-rejection phenomenon, marked by acceptance of musculoskeletal elements but rejection of the skin, has been consistently observed (10). Achieving stable, multilineage chimerism is required for tolerance of all VCA components; this has only been accomplished through intensified conditioning regimens incorporating augmented irradiation, CTLA4-Ig, anti-IL-6R therapy, and vascularized bone marrow, which enabled long-term tolerance of skin-bearing VCAs across class-I barriers in a clinically relevant model (11). Nonhuman primate data further underscore this divide: prior delayed-tolerance induction protocols in cynomolgus macaques generated robust renal tolerance under identical conditioning yet consistently failed in hand or face VCA models, with early rejection, infectious complications, and absence of chimerism (12). More recently, our group demonstrated, for the first time in the NHP partial face transplant model, that simultaneous tolerance induction can generate transient myeloid and lymphoid chimerism, allowing for prolonged immunosuppression-free survival of a face allograft, although the graft ultimately underwent split and then full rejection (13). Collectively, these findings highlight that VCA immunobiology differs substantially from that of solid organs, cautioning against the direct extrapolation of kidney-derived tolerance strategies to the multi-tissue context of VCA. Furthermore, the extreme sensitivity of these grafts to ischemia-reperfusion injury suggests that they may substantially benefit from ex vivo preservation, preconditioning and reengineering strategies (14), as also highlighted by Blein et al.Taken together, these organ-and species-specific distinctions, further magnified in VCA, underscore that tolerance strategies cannot simply be transferred from one graft type to another. They also outline multiple conceptual layers that shape tolerance-induction research and its clinical translation (Figure 1). Against this backdrop, the authors' effort to synthesize crossorgan tolerance mechanisms and to delineate shared versus organ-specific barriers is both timely and necessary, and their work represents a highly relevant contribution to the field.